The potential role of plant secondary metabolites on antifungal and immunomodulatory effect.

In addition to terpenoids, phenolics, and nitrogen-containing secondary compounds, plant-derived essential oils, also known as volatile oils, have attracted much attention for their antifungal activities. Essential oils are a mixture of secondary metabolites. Most are volatile aromatic oil-like liquids, containing aliphatic compounds, aromatic compounds, sulfur and nitrogen compounds, and terpenes and their oxygen derivatives. Since 1987, more than 500 articles have reported on the antifungal properties of essential oils (Kalemba and Kunicka 2003 ). Essential oils have been listed as the most widely used special plant metabolites due to their anti-infective properties (Plant et al. 2019 ). Investigations have shown that essential oils have significant antifungal effects, not only on deep fungal infections caused by Aspergillus and Candida , but also on superficial fungal infections caused by Microsporum canis , M. gypseum , T. rubrum , and T. mentagrophytes , and even on phytopathogenic fungi in crops (Bakkali et al. 2008 ; Danielli et al. 2018 ). The antifungal targets of essential oils mainly involve inhibition of fungal cell growth and mycotoxin synthesis, for example, by disruption of cell membrane permeability and intracellular electron transport chains, resulting in intracellular metabolic disorders (Mirza Alizadeh et al. 2022 ). Investigations have found that rosemary ( Rosmarinus officinalis ) essential oil not only targets mycelial ergosterol synthesis to inhibit toxin biosynthesis in A. flavus , but also inhibits mycelium growth to play an antifungal effect on the phytopathogen F. oxysporum (da Silva Bomfim et al. 2020 ; Hussein et al. 2020 ). Furthermore, Rhododendron tomentosum essential oils not only have an inhibitory effect on Candida parapsilosis , but also play an antifungal role in affecting the permeability of cell membranes in the yeast, Saccharomyces cerevisiae (Judzentiene et al. 2020 ). The concentrations of thyme essential oil and ginger essential oil were 11.25 μg/mL and 364 μg/mL, respectively, which exerted a marked antifungal effect on Fusarium and an inhibitory effect on the synthesis of Fusarium mycotoxins such as deoxypyrimethamine and zearalenone (Romoli et al. 2022 ). In addition to extensive antibacterial activity, Bupleurum rigidum essential oil can also play an antifungal role by changing the ultrastructure of C. albicans , C. neoformans , and T. rubrum (Zuzarte et al. 2021 ). Melaleuca alternifolia essential oil, which is mainly pinene-4-alcohol, showed antifungal activity in vitro against A. niger and both azole-sensitive and azole-resistant C. albicans (Hammer et al. 2002 ; Kumar 2020 ); in the rat vaginal C. albicans infection model, this essential oil also had a great impact on eliminating C. albicans infection and enhancing the anti-infection ability (Mondello et al. 2006 ). Oregano oil at a concentration of 0.25 mg/mL completely inhibited the growth of C. albicans in vitro. In addition, it also inhibited spore germination and mycelium growth in a concentration-dependent manner (Manohar et al. 2001 ). In vivo, the survival rate of the mice was as high as 80% after continuous treatment with oregano oil for 30 days in a mouse systemic candidiasis model, whereas the fungal load in mouse kidney tissue was close to zero (Manohar et al. 2001 ). Sodium houttuyfonate (SH), a volatile oil from Houttuynia cordata , exerted an antifungal effect on C. albicans by affecting gene expression in the Ras1-cAMP-Efg1 pathway and decreasing biofilm formation and the production of cAMP. Compared with the infected group, the survival rate of the SH-treated group was significantly higher in the experimental model of Galleria mellonella caterpillars (Wu et al. 2020 ). In addition, our previous investigation also found that sodium new houttuyfonate (SNH), which were modified compounds of SH, had a marked antifungal effect on A. fumigatus . SNH achieves antifungal effects by inhibiting the synthesis of ergosterol in the cell membrane of A. fumigatus . In addition, in a mouse model of systemic A. fumigatus infection, SNH treatment significantly reduced the fungal load in the tissues (Zhang et al. 2022b ). Studies have also found that essential oils can synergistically improve the antifungal effect when combined with existing antifungal drugs. For example, the combination of oregano essential oil and winter savory essential oil with the synthetic antifungal drug clotrimazole significantly reduced the metabolic activity of C. glabrata . At the same time, low concentrations of winter savory essential oil combined with clotrimazole caused organellar disorder in this fungus, with autophagic vacuoles, whereas high concentrations of winter savory essential oil combined with clotrimazole caused complete destruction of C. glabrata organelles (Massa et al. 2018 ). Recent investigations have also reported that peppermint essential oil could alleviate the excessive inflammation exhibited by LPS-induced RAW264.7 cells by inhibiting the ERK/NF-κB pathway and the gene expression of COX-2 , iNOS , IL-6 , and IL-1β (Kim et al. 2021 ). It also found that the essential oil from Citrus flower blocked the MAPK signaling pathway by inhibiting the phosphorylation of p38 and JNK and downregulating the gene expression of IL-6 , IL-1β , and TNF-α in RAW264.7 cells (Shen et al. 2017 ). In addition, Lanxangia tsaoko (black cardamom, formerly Amomum tsao-ko ) essential oil could reduce the activation of the NLRP3 inflammasome by inhibiting the production of Caspase-1 and downregulate the expression of inflammatory mediators iNOS and COX-2 by inhibiting the activation of JAK/STAT and the processing of IL-1β and pyroptosis in THP-1 cells (Chen et al. 2017 , 2021 ). Like dexamethasone, 1-h early injection of lavender essential oil had a therapeutic effect in the rat model of kappa-carrageenan-induced pleurisy. Further research found that the volume and total protein concentration of the exudate collected from the rats were both significantly reduced, while the total numbers of leukocytes and polymorphocytic leukocytes migrating into the pleural cavity were also reduced (Silva et al. 2015 ). This phenomenon also occurred in an animal model of carrageenan-induced pleurisy treated with rosemary essential oil. Investigations found that rosemary essential oil could induce leukocyte migration in vivo as well as induce chemotaxis in vitro. Recent studies found that dietary supplementation of rosemary essential oil significantly reduced MPO activity and IL-6 level in a 2,3,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis mouse model (Borges et al. 2019 ). The effect of Citrus bergamia (bergamot orange) essential oil on acne vulgaris was explored in the Mesocricetus auratus (golden hamster) model. It was found that the serum levels of IL-1α and TNF-α decreased in response to the oil in a dose-dependent manner after treatment (Sun et al. 2020 ). Recently, nutmeg ( Myristica fragrans ) essential oil extract was found to have anti-inflammatory activity in rodents, associated with reduced release of COX-2 and P-substances in the blood, as well as reduction of joint swelling induced by Freund’s adjuvant injection in rats (Ashokkumar et al. 2022 ; Zhang et al. 2016a ). Moreover, intragastric administration of SNH could significantly reduce fungal load in tissues and exerted anti-inflammatory effects through downregulating the production of inflammatory cytokines IL-6 and IL-17A in a mouse model of systemic A. fumigatus infection (Zhang et al. 2022b ). Peppermint essential oil has marked anti-inflammatory effect, not only inhibiting NO and PGE2 production in LPS-activated RAW264.7 cells, but also inhibiting the production of NO and PGE2 on croton oil-induced ear edema in mice (Sun et al. 2014 ). Because of the antifungal potential of some essential oils when used alone or in combination, and of the efficacy of some essential oils in regulating inflammation, plant-derived essential oils also have great development potential in antifungal applications.

This review first briefly summarizes the current situation of clinical antifungal treatments of common superficial and deep fungal infections, the antifungal mechanisms of existing antifungal drugs (Fig.  1 A), and their immunomodulatory effects on the host. At present, although there are few types of antifungal drugs and their targets, antifungal drugs can better help treat fungal infections by regulating the secretion of pro-inflammatory or anti-inflammatory factors to regulate the immune function of the host. So, can plant secondary metabolites cause similar effects? The mode of action of different antifungal plant secondary metabolites against various pathogenic fungi and the immunomodulatory effects of plant metabolites on the host were further reviewed. The antifungal mechanisms of plant secondary metabolites primarily include (1) inhibition of fungal mycotoxin synthesis; (2) prevention of fungal biofilm formation and destruction of the established fungal biofilm; (3) decrease in the number of spores and the growth of hyphae; (4) prevention of ergosterol synthesis, disruption of cell membrane permeability, and promotion of cell wall destruction and lysis; and (5) alteration of cellular DNA replication and disruption of the cell cycle (Fig.  1 B). At the same time, it was found that many plant secondary metabolites also reduced tissue inflammation and played an immunoregulatory function by reducing the release of pro-inflammatory factors (Table 2 ). In summary, many plant secondary metabolites have both antifungal and immunomodulatory effect (Fig.  2 ). And most of them have been used in clinical therapy independently or combined with existing antifungal drugs to better exert antifungal effects (Table 3 ). Therefore, plant secondary metabolites have broad prospects for the development of novel antifungal drugs. Fig. 1 Mechanism of antifungal action of existing antifungal drugs and plant secondary metabolites. A Antifungal targets had been confirmed in the existing antifungal drug. Existing antifungal agents include allylamines, azoles, polyalenes, echinocins, and flucytosine. B Antifungal targets had been confirmed in the plant secondary metabolites. The antifungal pathway of plant secondary metabolites include (1) prevention of fungal biofilm formation and destruction of the established fungal biofilm; (2) alteration of cellular DNA replication and disruption of the cell cycle; (3) inhibition of fungal mycotoxin synthesis; (4) prevention of ergosterol synthesis, disruption of cell membrane permeability, and promotion of cell wall destruction and lysis; and (5) decrease in the number of spores and the growth of hyphae Table 2 Regulatory immune mechanisms of plant secondary metabolites in vitro and in vivo Classification Name of active compounds/secondary metabolites Experimental model Mechanism of action Reference Alkaloid Aconitine Rat Inhibit the activation of NF-κB and the production of TNF-α, IL-6, and IL-1β Wang et al. ( 2019c ) Berberine Mice Reduce the synthesis of COX-2 and PGE2 Yao et al. ( 2019 ) Rat Inhibit the secretion of TNF-α, IL-8, IL-6, and MCP-1 Yu et al. ( 2019 ) CD4 + T cells Activate AMPK signal pathway Takahara et al. ( 2019 ) Matrine Mice downregulate the expression of CD14 and TLR4 Li et al. ( 2020b ) Mouse airway epithelial cells Inhibit the production of SOCS3 and ROS by NF-κB signal pathway Li et al. ( 2019 ) THP-1 cells Negative regulate the secretion of TNF-α, IL-8, and IL-1α Zhou et al. ( 2019 ) Sinomenine Rat Inhibit the activities of iNOS and COX-2 Zhu et al. ( 2019 ) Phenolics Gingerol Human intestinal epithelial cell Increase the expression of Nrf2 and the level of the antioxidant reduced glutathione and decrease the concentration of ROS Mao et al. ( 2019 ) RAW264.7 cell Inhibit the production of NO and PGE2 Zhang et al. ( 2013 ) Quercetin RAW264.7 cell Inhibit PI3K phosphorylation and TLR4/MyD88/PI3K complex formation via Src and Syk Domínguez-Avila et al. ( 2022 ) Lung A549 cell Inhibit the production of IL-8 Geraets et al. ( 2007 ) Microglia Inhibit the production of TNF-α Bureau et al. ( 2008 ) Broiler chickens Activate the NF-κB signal pathway Yang et al. (2020b) Resveratrol Microglia Inhibit the production of TNF-α and IL-1 Bureau et al. ( 2008 ) Ferulic acid Bovine uterine epithelial endometrial cell Inhibit the production of IL-1β, IL-6, IL-8, and TNF-α by IκB/ NF-κB/MAPK signal pathway Yin et al. ( 2019 ) Terpenes Geniposide RAW264.7 cell Inhibit the activation of NF-kB and expression of IFN-γ and iNOS Koo et al. ( 2004 ) Laurene Human chondrocytes Inhibit the activation of NF-κB, JNK, ERK1/2, and p38 Rufino et al. ( 2015 ) Quinoa saponin RAW264.7 cell Downregulate the expression of TNF-α , IL-6 and iNOS Yao et al. ( 2014 ) Soybean saponins RAW264.7 cell Inhibit the degradation of IκBα and activation of NF-κB, and the production of COX-2, iNOS, MCP-1, and TNF-α Kang et al. ( 2005 ) β-patchoulene Mice Inhibit the production of IL-6, TNF-α, and IL-1β, and the expression of iNOS and COX-2 Zhang et al. ( 2016b ) Other plant secondary metabolites Lavender essential oil Rat Reduce inflammatory exudates Silva et al. ( 2015 ) Rosemary essential oil Mice Inhibit the activity of MPO and the level of IL-6 Borges et al. ( 2019 ) Citrus bergamia essential oil Syrian hamster Inhibit the secretion of IL-1α and TNF-α Sun et al. ( 2020 ) Lanxangia tsaoko essential oil THP-1 cells Inhibit the production of Caspase-1, the activation of JAK/STAT, and the expression of iNOS and COX-2 Chen et al. ( 2017 ); Chen et al. ( 2021 ) Nutmeg essential oil Rat Inhibit the expression of COX-2 and the release of P -substance Ashokkumar et al. ( 2022 ); Zhang et al. ( 2016a ) Peppermint essential oil Mice Inhibit the production of NO and PGE2 Sun et al. ( 2014 ) RAW264.7 cell Inhibit the ERK/NF-κB signaling pathway and the expression of COX-2 , iNOS , IL-6 , and IL-1β Kim et al. ( 2021 ) Essential oil from Citrus flower RAW 264.7 cell Blocked the MAPK signaling pathway and downregulate the expression of IL-6 , IL-1β , and TNF-α Shen et al. ( 2017 ) Sodium new houttuyfonate Mice Inhibit the secretion of IL-6 and IL-17A Zhang et al. ( 2022b ) AMPK adenosine 5′-monophosphate (AMP)-activated protein kinase, Caspase-1 cysteinyl aspartate-specific proteinase, COX-2 cyclooxygenase-2, ERK extracellular regulated protein kinases, GM-CSF granulocyte–macrophage colony stimulating factor, GSH gonad-stimulating hormone, iNOS inducible nitric oxide synthase, IL-1 interleukin-1, IL-6 interleukin-6, IL-8 interleukin-8, IL-17A interleukin-17A, INF-γ interferon-gamma, IκB inhibitor of NF-κB, JNK c-Jun N-terminal kinase, JAK janus kinase, MAPK mitogen-activated protein kinase, MCP-1 monocyte chemoattractant protein-1, MPO myeloperoxidase, Myd88 myeloid differentiation factor 88, NF-κB nuclear factor kappa-B, NO nitric oxide, Nrf2 nuclear factor erythroid 2, NLRP3 nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3, PGE2 prostaglandin E2, PI3K phosphatidylinositol-3-kinase, p38 phosphorylated p38 mitogen-activated protein kinase, ROS reactive oxygen species, SOCS3 recombinant suppressors of cytokine signaling 3, STAT signal transducer and activator of transcription, Src nonreceptor tyrosine kinase c, Syk spleen tyrosine kinase, TNF tumor necrosis factor; TLR4 toll-like receptor 4 Fig. 2 Summary of plant secondary metabolites with both antifungal and immunomodulatory effect. These compounds are derived from alkaloids, phenols, terpenoids, and other plant secondary metabolites, respectively Table 3 Summary of plant secondary metabolites that have been used clinically or have synergistic effects with existing antifungal drugs Classification Name of active compounds/secondary metabolites Clinical application research Fungus In combination Synergistic effects In vivo Reference Alkaloids Magnoflorine  −  C. albicans , T. rubrum MCZ  +   −  Kim et al. ( 2018 ) Berberine Improve insulin resistance C. albicans AmB, FLC, VRC, CAS  +  Mice Han and Lee ( 2005 ); Imenshahidi and Hosseinzadeh ( 2019 ) Phenolics Propolis Anti-viral treatment A. niger , C. albicans  −   −  Rat Ali and Kunugi ( 2021 ); Freires et al. ( 2016 ) Curcumin Treatment and prevention of type 2 diabetes A. flavus AmB, ITR  +   −  Pivari et al. ( 2019 ); Rocha et al. ( 2021 ) Baicalin Treatment of pancreatic injury C. albicans , A. fumigatus , T. rubens , T. trichophyton FLC  +   −  Wang et al. ( 2015 ); Wen et al. ( 2020 ) Quercetin Treatment of metabolic diseases A. fumigatus AmB, FLC  +  Mice Yi et al. ( 2021 ); Yin et al. ( 2021 ) Terpenes Limonene Dissolve cholesterol in gallstones and prevent cancer C. albicans , A. fumigatus , C. neoformans , T. rubrum , T. mentagrophytes FLC, AmB  +  Mice Nidhi et al. ( 2020 ); Sun ( 2007 ) Citronellal  −  C. albicans , Penicillium AmB, FLC  +  Rat Liu et al. ( 2021 ) Geraniol Treatment for irritable bowel syndrome C. albicans , A. niger , A. flavus AmB, FLC, KET  +   −  Ricci et al. ( 2022 ); Shin ( 2003 ) Thymol Adjuvant treatment of periodontitis C. albicans , C. tropicalis AmB, FLC  +  Mice Anand et al. ( 2012 ); Jafri and Ahmad ( 2020 ) Other secondary metabolites Rosemary essential oil Treatment of Raynaud’ s phenomena associated with systemic sclerosis A. flavus , F. oxysporum  −   −   −  Vagedes et al. ( 2022 ) Thyme essential oil Treatment of helicobacter pylori infection Fusarium , C. albicans  −   −   −  Nikolić et al. ( 2023 ) Melaleuca alternifolia essential oil Improve photoaged skin A. niger , C. albicans  −   −  Mice Hugo Infante et al. ( 2023 ); Mondello et al. ( 2006 ) Sodium houttuyfonate  −  C. albicans FLC  +  Mice Chen et al. ( 2022b ) Sodium new houttuyfonate  −  A. fumigatus, C. albicans FLC, CAS, ITR  +  Mice, Galleria mellonella Wu et al. ( 2020 ); Zhang et al. ( 2022b ) AmB amphotericin B, CAS caspofungin, FLC fluconazole, ITR itraconazole, KET ketoconazole, MCZ miconazole, VRC voriconazole, “ − ”, no study were mentioned in the corresponding references; “ + ”, synergistic or additive action Mechanism of antifungal action of existing antifungal drugs and plant secondary metabolites. A Antifungal targets had been confirmed in the existing antifungal drug. Existing antifungal agents include allylamines, azoles, polyalenes, echinocins, and flucytosine. B Antifungal targets had been confirmed in the plant secondary metabolites. The antifungal pathway of plant secondary metabolites include (1) prevention of fungal biofilm formation and destruction of the established fungal biofilm; (2) alteration of cellular DNA replication and disruption of the cell cycle; (3) inhibition of fungal mycotoxin synthesis; (4) prevention of ergosterol synthesis, disruption of cell membrane permeability, and promotion of cell wall destruction and lysis; and (5) decrease in the number of spores and the growth of hyphae Regulatory immune mechanisms of plant secondary metabolites in vitro and in vivo AMPK adenosine 5′-monophosphate (AMP)-activated protein kinase, Caspase-1 cysteinyl aspartate-specific proteinase, COX-2 cyclooxygenase-2, ERK extracellular regulated protein kinases, GM-CSF granulocyte–macrophage colony stimulating factor, GSH gonad-stimulating hormone, iNOS inducible nitric oxide synthase, IL-1 interleukin-1, IL-6 interleukin-6, IL-8 interleukin-8, IL-17A interleukin-17A, INF-γ interferon-gamma, IκB inhibitor of NF-κB, JNK c-Jun N-terminal kinase, JAK janus kinase, MAPK mitogen-activated protein kinase, MCP-1 monocyte chemoattractant protein-1, MPO myeloperoxidase, Myd88 myeloid differentiation factor 88, NF-κB nuclear factor kappa-B, NO nitric oxide, Nrf2 nuclear factor erythroid 2, NLRP3 nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3, PGE2 prostaglandin E2, PI3K phosphatidylinositol-3-kinase, p38 phosphorylated p38 mitogen-activated protein kinase, ROS reactive oxygen species, SOCS3 recombinant suppressors of cytokine signaling 3, STAT signal transducer and activator of transcription, Src nonreceptor tyrosine kinase c, Syk spleen tyrosine kinase, TNF tumor necrosis factor; TLR4 toll-like receptor 4 Summary of plant secondary metabolites with both antifungal and immunomodulatory effect. These compounds are derived from alkaloids, phenols, terpenoids, and other plant secondary metabolites, respectively Summary of plant secondary metabolites that have been used clinically or have synergistic effects with existing antifungal drugs AmB amphotericin B, CAS caspofungin, FLC fluconazole, ITR itraconazole, KET ketoconazole, MCZ miconazole, VRC voriconazole, “ − ”, no study were mentioned in the corresponding references; “ + ”, synergistic or additive action There are an estimated 420,000 plant species in nature, and some of them have been used as traditional herbal medicines to treat diseases since ancient times (Wang et al. 2021c ). Generally, plant extracts are complex mixtures, and their active ingredients vary according to plant species, chemical types, and extraction methods. Each ingredient may have multiple targets in the body. Therefore, it is still necessary to explore the specific mechanisms of individual antifungal plant metabolites against fungi or for immunoregulation in vivo. Additionally, the development of antifungal and immunomodulatory drugs from plant secondary metabolites is still at the preliminary stage. The available clinical references are extremely scarce, and such drugs are still a long way from being used in the clinic. Therefore, what techniques should be used to extract plant secondary metabolites, which secondary metabolites have antifungal or broad-spectrum antifungal effects, how do they affect the immune status of the host body, and can they be used as antifungal or immunomodulatory drugs in clinical? All these issues need to be addressed urgently. It is up to more funding institutions and researchers to invest more human and material resources into exploring the vast “plant kingdom.”

Fungal infections are characterized by high morbidity and mortality. Every year, at least 1.5 million people are killed, and the lives of more than one billion people are affected by fungal infections (Bongomin et al. 2017 ). In recent years, the frequency of fungal infections has been increasing rapidly. Fungal infections can be divided into superficial and deep infections. Deep fungal infections can cause invasive mycosis, which is an infectious disease caused by fungal invasion of subcutaneous tissues, mucous membranes, and internal organs. About 6 in 100,000 people are infected with invasive fungi each year, although only one-half of fatal cases are diagnosed prior to death (Dignani 2014 ). Therefore, the lack of timely diagnosis, and treatment, is one of the causes of the high mortality of invasive fungal infections (von Lilienfeld-Toal et al. 2019 ). At present, invasive fungal infections are mainly caused by species of Aspergillus , Candida , and Cryptococcus (Pathakumari et al. 2020 ), and echinomycin, flucytosine, polyenes, and triazoles are the drugs used most commonly for their treatment. Superficial fungal infections can lead to cutaneous mycosis and superficial mycosis, which are caused by pathogenic fungi parasitizing keratin tissues, such as hair, nails, and skin. Cutaneous mycosis is one of the most common superficial fungal infections, with an incidence of up to 25% (Havlickova et al. 2008 ). Cutaneous mycosis is also known as “ringworm.” Ringworm infections are caused mainly by species of Epidermophyton , Microsporum , and Trichophyton , with the common skin ringworm infection in human being caused by Trichophyton rubrum . At present, topical drugs used to treat superficial fungal infections include allylamines, azoles, and griseofulvin (Ademe 2020 ; Khurana et al. 2019 ). Because of the increased incidence of fungal infections, the limited range of antifungal drugs available in clinics, and the emergence of drug-resistant or multi-drug-resistant fungal strains, the successful treatment of patients with a fungal infection is a challenging issue. For example, multi-drug-resistant Candida auris has become one of the major threats to global public health security (Du et al. 2020 ). At the same time, with the emergence of azole-resistant Aspergillus strains, Aspergillus infections have gradually become one of the global public health concerns (Zhang et al. 2021b ). During the coronavirus disease 2019 (COVID-19) pandemic, it was found that the number of patients with COVID-19 complicated by Aspergillus infection was as high as 23.3% (Lai and Yu 2021 ). In addition, drug-resistant fungal strains are not limited to deep fungal infections, but are also rapidly increasing in association with superficial fungal infections (Saunte et al. 2019 ). It had found that the incidence of terbinafine-resistant superficial fungal strains ranged from 16 to 77% in India (Singh et al. 2020 ). Therefore, in order to solve these problems, efforts should be made to develop new antifungal drugs or fungal inhibitors. In Chinese literature, from Shen Nung, who tested hundreds of grasses, to Li Shizhen’s “Compendium of Materia Medica,” plants and their derivatives have been successfully used in practice in medicine. For instance, the development of the antimalarial drugs quinine and artemisinin from plants are well-established examples (Achan et al. 2011 ; Ma et al. 2020 ). Prescriptions of traditional herbal remedies are still used today, using various active compounds in preparations extracted from plants to treat a range of diseases. Plant secondary metabolites represent an enormous range of small molecular organic compounds developed during the long-term evolution of plants, which are generally not directly involved in plant survival, but which fulfill secondary roles, such as defense chemicals, attractant pigments and fragrances, and plant hormones or growth regulators (Erb and Kliebenstein 2020 ). At present, research on plant metabolites (primary and secondary) is increasing, although research on the antifungal properties of plant metabolites is still mainly focused on plant secondary metabolites (Mickymaray 2019 ). More than 200,000 different plant secondary metabolites have been isolated and identified. According to the biosynthetic pathways involved, plant secondary metabolites include nitrogenous organic substances (such as alkaloids, cyanogenic glucosides, and non-protein amino acids), phenolics and terpenoids, as well as other secondary metabolites such as essential oils (Loi et al. 2020 ). The successful development of drugs derived from plant secondary metabolites has resulted in better treatment of cardiovascular diseases, malignant tumors, and neurodegenerative diseases (Table 1 ). Table 1 Plant secondary metabolites in the prevention and treatment of diseases Classification Name of active compounds/secondary metabolites Prevention and treatment of diseases Reference Alkaloid Berberine Atherosclerosis, depression, diabetes, gastric cancer, lymphoma Ma et al. ( 2022a ); Qu et al. ( 2021 ); Ren et al. ( 2021 ); Zhang et al. ( 2021a ); Zhang et al. ( 2020 ) Matrine Acute myeloid leukemia, anti-oxidation, anti-inflammation, atherosclerosis, cervical cancer, diabetes, liver cancer Guo et al. ( 2021 ); Liu et al. ( 2017 ); Wang et al. ( 2021b ); Zhang et al. ( 2022a ); Zhou et al. ( 2022 ) Neferine Diabetes, hypertension, pulmonary hypertension Wicha et al. ( 2020 ); Xiao et al. ( 2022 ); Zhang et al. ( 2018 ) Trigonelline Atherosclerosis, diabetes Anwar et al. ( 2018 ); Zhao et al. ( 2021 ) Vincristine Breast cancer Wang et al. ( 2017 ) Phenolics Curcumin Anti-inflammation, breast cancer, endometriosis (endometrial cancer), rectal cancer Jahanbakhshi et al. ( 2021 ); Moradi-Marjaneh et al. ( 2018 ); Wang et al. ( 2019b ); Zhang et al. ( 2019 ) Ellagic acid Anti-inflammation, esophageal squamous cell carcinoma, immunoregulation, pancreatic cancer Cheng et al. ( 2017 ); Gu et al. ( 2014 ); Xu et al. ( 2020 ) Quercetin Anti-inflammation, antioxidant, anti-aging, depression, liver cancer Cui et al. ( 2022 ); Han et al. ( 2021 ); Lu et al. ( 2018 ); Tang et al. 2019 ; Wu et al. ( 2019 ) Rosmarinic acid Antioxidant, anti-inflammatory, depression, liver cancer, ovarian cancer Cao et al. ( 2016 ); Cui et al. ( 2022 ); Lim et al. ( 2020 ); Verma et al. ( 2022 ) Shogaol Anti-inflammation, cervical cancer, leukemia, oral cancer Annamalai and Suresh ( 2018 ); Han et al. ( 2017 ); Liu et al. ( 2013 ); Pei et al. ( 2021 ) Tea polyphenols Antioxidant, atherosclerosis, cholangiocarcinoma, skin cancer Kumar et al. ( 2012 ); Quezada-Fernandez et al. ( 2019 ); Wang et al. 2018 ; Zhu et al. ( 2021 ) Terpenes Andrographolide Anti-inflammation, breast cancer, diabetes, rectal cancer Burgos et al. ( 2020 ); Li et al. ( 2020a ); Paul et al. ( 2021 ); Peng et al. ( 2018 ) Ganoderma triterpenes Anti-inflammation, anti-tumor, antioxidant Liu et al. ( 2015 ); Sliva et al. ( 2012 ); Wang et al. ( 2019a ) Geraniol Antioxidant, anti-inflammation, anti-tumor, cardiovascular disease Jayachandran et al. ( 2015 ); Polo and de Bravo ( 2006 ); Wang et al. ( 2016 ) Paeoniflorin Alzheimer’s disease, anti-inflammation, antioxidant, immunoregulation Kong et al. ( 2020 ); Wen et al. ( 2019 ); Zhang and Wei ( 2020 ) Radix Bupleuri Anti-inflammation, atherosclerosis, liver cancer Du et al. ( 2018 ); Jiang et al. ( 2020 ); Luo et al. ( 2020 ) Taxol Breast cancer, lung cancer, ovarian cancer, peripheral arterial disease Krawisz et al. ( 2021 ); Scribano et al. ( 2021 ); Weaver ( 2014 ); Wu et al. ( 2018 ) Other secondary metabolites Citrus bergamia essential oil Degenerative diseases Scuteri et al. ( 2019 ) Mastic oil Anti-inflammation, antioxidant, colon cancer, lung adenocarcinoma Ostovan et al. ( 2020 ); Serifi et al. ( 2019 ); Spyridopoulou et al. ( 2017 ) Rosemary essential oil Degenerative neurological diseases, hypertension Fernandez et al. ( 2014 ); Sasaki et al. ( 2021 ) Plant secondary metabolites in the prevention and treatment of diseases Invasive pathogens often occur in people with compromised immunity (Xie et al. 2022 ). Therefore, antifungal agents could act by either having a direct antifungal (fungicidal or fungistatic) effect on pathogenic fungi or playing a role in upregulating a patient’s immunity (Arastehfar et al. 2020 ; Lei et al. 2023 , 2022 ). There is an urgent need to develop new antifungal drugs, drugs that help to increase the activity of existing antifungal drugs, or drugs with immunomodulatory effects on the host. Additionally, many plant secondary metabolites had been confirmed to show antifungal activity or greatly increase the antifungal action of existing antifungal drugs by synergistic action (Ganesan and Xu 2017 ; Loi et al. 2020 ). However, compared with investigations on bacterial infectious diseases of humans, there has been a few review about the role of plant extracts or their components in the treatment of fungal infections. Therefore, more attention needs to be paid to the treatment of fungal infections with plant preparations or individual plant secondary metabolites.